The prevalence of type 2 diabetes (T2DM) has been increasing at epidemic proportions worldwide including significantly increased rates among United States (US) minority populations such as Mexican Americans. To date, knowledge about the genetic determinants of T2DM is very limited. However, recent genome-wide association studies (GWASs) of T2DM in populations of European ancestry have localized 19 putative genomic regions that may harbor relevant susceptibility loci. These initial findings reflect association signals related to common variants. The identity of the underlying causal genes and their functional variants still remain unknown. Efforts to replicate the original association findings in ethnically diverse populations have not been universally successful, perhaps due to issues such as allele frequency and linkage disequilibrium (LD) differences. Therefore, an exhaustive resequencing-based search of the genomic regions surrounding these original genetic signals in ethnically diverse populations is required to help identify the underlying causal genes and their likely functional variants. In the proposed project, we will attempt to identify causal variants influencing T2DM based on existing localizations obtained from GWA studies using data/samples from five Mexican American family studies in San Antonio (N = 5,638). To fulfill our objective, we will identify all sequence variants in an approximately 250 kb region around the single nucleotide polymorphism (SNP) of interest by deep resequencing of the selected 16 T2DM candidate gene regions identified from GWASs (Aim 1). Using a highly efficient family-based design, we will then identify the most likely functional variants influencing risk of T2DM in 1,000 effectively sequenced individuals using a novel statistical prioritization method, Bayesian quantitative trait nucleotide (BQTN). The most strongly associated 50 SNPs from Aim 2 will then be typed in a sample of 5,030 adults to confirm their association with T2DM (Aim 3). In addition, we will examine whether the variants found to be significant in adults affect T2DM related traits in ~600 non-diabetic children. To carry out the study, advanced next generation sequencing techniques will be combined with unique computationally intensive statistical genetic techniques to predict those variants most likely to play causal roles in T2DM risk. RELEVANCE: Identification of T2DM susceptibility genes in Mexican Americans will have major public health relevance in the US and in developed and developing countries. Identification of genes causally involved in T2DM risk may dramatically speed the quest for novel drug targets and improved pharmacologic interventions. Genetic findings in Mexican Americans may help explain health disparities among US populations.